Biomaterial enhancement of stem cell transplant efficacy for macular degeneration No effective therapies yet exist for advanced macular degeneration. Restoring vision in severe cases requires replacing both retinal pigmented epithelium (RPE) and photoreceptors because photoreceptors require functional RPE to survive. However, no approach to replace both cell types has yet been introduced. Further, previous attempts to replace photoreceptors have met limited success in rodent models, likely because of low survival rates and restricted distribution of transplanted cells. This project integrates solutions to both of these challenges: we propose to transplant human embryonic stem (ES) cell-derived primitive retinal stem cells (hpRSCs), a cell population that is more pluripotent than cell types previously transplanted to restore vision. We have shown that hpRSCs yield both RPE and photoreceptors in vitro and in vivo; replacing both cell types in vivo would yield longer-lasting visual improvements, as transplant-derived RPE would support transplant-derived photoreceptors. In order to develop a maximally effective therapy, we will deliver hpRSCs in an injectable hydrogel whose biochemistry and mechanics closely match those of the ocular extracellular matrix, which has recently been shown to uniformly distribute transplanted cells across the retina. This project stands to position ES cell-derived RPCs for translation into the clinic. The key to this advance is the collaboration between the PIs, bringing together a leader in macular degeneration models and the differentiation of stem cells into retinal neurons (Zhang) with a biomaterials research group (Almutairi). The Zhang group's expertise will ensure that this project advances development of HAMC for ocular transplantation significantly: previous work has not employed relevant animal models, so the impact of the material on transplanted cells' differentiation and functional recovery has not yet been assessed. Further, it has relied on cells that are easiest to derive, whereas this project will employ ES cell-derived RPCs, which are the only clinically viable option. By completion of this project, we expect to: 1. Assess the effect of HAMC delivery on survival and distribution of subretinally injected retinal stem cells 2. Define the effect of HAMC on the ability of retinal stem cells to differentiate into RPE and photoreceptors in vitro and in vivo 3. Identify the delivery method that maximizes visual improvement ensuing from subretinal injection of retinal stem cells in Royal College of Surgeons (RCS) rats